The NHLBI-sponsored PITCH-HF trial (#U01HL105562) will begin enrollment in Q1 2013. PITCH-HF is the first well-controlled, randomized, large-scale (n=2,012) trial studying the effect of tadalafil, an FDA-approved selective phosphodiesterase type 5 inhibitor (PDE5i), on cardiovascular (CV) deaths and heart failure (HF) hospitalizations in patients with left ventricular systolic dysfunction and secondary pulmonary hypertension. The biology of PDE5i strongly suggests a potential renoprotective effect, but PITCH-HF currently lacks renal endpoints. Both chronic kidney disease (CKD) (reflected by albuminuria and reduced glomerular filtration rate [GFR]) and acute kidney injury (AKI) significantly contribute to morbidity and mortality in patients with CV disease and HF. We expect e30% of participants in PITCH-HF will develop one or more of these endpoints over the study period. Therapies that alter the course of renal disease in patients with HF are sorely lacking. This application requests modest funding for PITCH-ER, an ancillary study to address two major patient- oriented questions: (1) Does chronic tadalafil treatment slow the rate of GFR decline and/or modify the development/progression of albuminuria vs placebo? We will examine longitudinal measures of eGFR (utilizing state-of-the-art equations that incorporate serum creatinine and cystatin C) and spot urine albumin-to- creatinine ratios; (2) Does PDE5i treatment reduce AKI frequency and/or the magnitude of urinary biomarker changes reflecting subclinical renal injury vs placebo? Using an AKI adjudication committee, we will monitor the incidence of AKI events and their severity using the latest KDIGO consensus criteria for AKI. We will also detect subclinical renal injury using the validated urinary biomarkers: neutrophil gelatinase-associated lipocalin and kidney injury marker 1. We expect that 30% of the overall PITCH-HF population will have diabetes, which amplifies the risk for renal injury in HF patients, thus, we include in this proposal a plan to repeat our analyses stratified by baseline diabetes status as Sub-Aims 1 and 2 should treatment effects differ between those with and without diabetes. The parent study lacks urine collection and modern measures of GFR such as serum cystatin C, and will not examine decline in GFR or frequency of AKI episodes during the study period. Thus, this proposal is particularly time-sensitive. By taking advantage of the PITCH-HF infrastructure and randomization, this ancillary study provides an efficient, economical, and well-powered approach to identify potential renoprotective effects of PDE5 inhibition. Our collaborative team has experience in performing high quality ancillary studies with renal endpoints, and collection and testing of biological samples from such studies utilizing state-of-the-art measures of renal function and biology. Our aims are well-powered and focus on well- defined endpoints, allowing us to answer important clinical and scientific questions with minimal burden to subjects and the parent study. The PITCH-HF Executive Committee and the NHLBI reviewers agree this proposal may radically shift the clinical care paradigm for patients with CKD, AKI, and CHF.